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Emergence of Hybrid Resistance and Virulence Plasmids Harboring New Delhi Metallo-β-Lactamase in Klebsiella pneumoniae in Russia.

ABSTRACT: The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) is a new threat to healthcare. In this study, we analyzed nine CR-hvKp isolates of different sequence-types (ST) recovered from patients with nosocomial infections in two hospitals in Saint Petersburg. Whole-genome sequencing showed that eight of them harbored large mosaic plasmids carrying resistance to carbapenems and hypervirulence simultaneously, and four different types of hybrid plasmids were identified. BLAST analysis showed a high identity with two hybrid plasmids originating in the UK and Czech Republic. We demonstrated that hybrid plasmids emerged due to the acquisition of resistance genes by virulent plasmids. Moreover, one of the hybrid plasmids carried a novel New Delhi metallo-beta-lactamase (NDM) variant, differing from NDM-1 by one amino acid substitution (D130N), which did not provide significant evolutionary advantages compared to NDM-1. The discovery of structurally similar plasmids in geographically distant regions suggests that the actual distribution of hybrid plasmids carrying virulence and resistance genes is much wider than expected.

SUBMITTER: Starkova P

PROVIDER: S-EPMC8226487 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Polymyxins are last-line antibiotics employed against multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance is rapidly on the rise globally. Polymyxins initially target lipid A of lipopolysaccharides (LPSs) in the cell outer membrane (OM), causing disorganization and cell lysis. While most studies focus on how genetic variations confer polymyxin resistance, the mechanisms of membrane remodeling and metabolic changes in polymyxin-resistant strains remain unclear, thus hampering the development of effective therapies to treat severe K. pneumoniae infections. In the present study, lipid A profiling, OM lipidomics, genomics, and metabolomics were integrated to elucidate the global mechanisms of polymyxin resistance and metabolic adaptation in a polymyxin-resistant strain (strain S01R; MIC of >128 mg/L) obtained from K. pneumoniae strain S01, a polymyxin-susceptible (MIC of 2 mg/L), New Delhi metallo-β-lactamase (NDM)-producing MDR clinical isolate. Genomic analysis revealed a novel in-frame deletion at position V258 of PhoQ in S01R, potentially leading to lipid A modification with 4-amino-4-deoxy-l-arabinose (L-Ara4N) despite the absence of polymyxin B. Comparative metabolomic analysis revealed slightly elevated levels of energy production and amino acid metabolism in S01R compared to their levels in S01. Exposure to polymyxin B (4 mg/L for S01 and 512 mg/L for S01R) substantially altered energy, nucleotide, and amino acid metabolism and resulted in greater accumulation of lipids in both strains. Furthermore, the change induced by polymyxin B treatment was dramatic at both 1 and 4 h in S01 but only significant at 4 h in S01R. Overall, profound metabolic adaptation was observed in S01R following polymyxin B treatment. These findings contribute to our understanding of polymyxin resistance mechanisms in problematic NDM-producing K. pneumoniae strains and may facilitate the discovery of novel therapeutic targets. IMPORTANCE Antimicrobial resistance (AMR) is a major threat to global health. The emergence of resistance to the polymyxins that are the last line of defense in so-called Gram-negative "superbugs" has further increased the urgency to develop novel therapies. There are frequent outbreaks of K. pneumoniae infections in hospitals being reported, and polymyxin usage is increasing remarkably. Importantly, the polymyxin-resistant K. pneumoniae strains are imposing more severe consequences to health systems. Using metabolomics, lipid A profiling, and outer membrane lipidomics, our findings reveal (i) changes in the pentose phosphate pathway and amino acid and nucleotide metabolism in a susceptible strain following polymyxin treatment and (ii) how cellular metabolism, lipid A modification, and outer membrane remodeling were altered in K. pneumoniae following the acquisition of polymyxin resistance. Our study provides, for the first time, mechanistic insights into metabolic responses to polymyxin treatment in a multidrug-resistant, NDM-producing K. pneumoniae clinical isolate with acquired polymyxin resistance. Overall, these results will assist in identifying new therapeutic targets to combat and prevent polymyxin resistance.

Project description:Outbreaks of infection occur more often than they are reported in most developing countries, largely due to poor diagnostic services. A Klebsiella species bacteremia outbreak in a newborn unit with high mortality was recently encountered at a location being surveilled for childhood bacteremia. These surveillance efforts offered the opportunity to determine the cause of this neonatal outbreak. In this report, we present the whole-genome sequences of New Delhi metallo-β-lactamase (NDM-5)-containing Klebsiella quasipneumoniae subsp. similipneumoniae bloodstream isolates from a neonatal bacteremia outbreak at a tertiary hospital in Nigeria and as part of the largest collection of K. pneumoniae bloodstream isolates from children in Africa. Comparative analysis of the genetic environment surrounding the NDM-5 genes revealed nearly perfect sequence identity to blaNDM-5-bearing IncX3-type plasmids from other members of the EnterobacteriaceaeIMPORTANCE Carbapenem-resistant Klebsiella pneumoniae is of global health importance, yet there is a paucity of genome-based studies in Africa. Here we report fatal blood-borne NDM-5-producing K. quasipneumoniae subsp. similipneumoniae infections from Nigeria, Africa. New Delhi metallo-β-lactamase (NDM)-producing Klebsiella spp. are responsible for high mortality and morbidity, with the NDM-5 variant showing elevated carbapenem resistance. The prevalence of NDM-5 in Klebsiella has been limited primarily to K. pneumoniae, with only one isolate being collected from Africa. During an outbreak of sepsis in a teaching hospital in Nigeria, five NDM-5-producing K. quasipneumoniae subsp. similipneumoniae sequence type 476 isolates were identified. Given the increased resistance profile of these strains, this study highlights the emerging threat of blaNDM-5 dissemination in hospital environments. The observation of these NDM-5-producing isolates in Africa stresses the urgency to improve monitoring and clinical practices to reduce or prevent the further spread of resistance.

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Emergence of Hybrid Resistance and Virulence Plasmids Harboring New Delhi Metallo-β-Lactamase in Klebsiella pneumoniae in Russia.

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